Blood Retainable Device Exhibiting Selective Degradability in Tumor Tissue

Abstract

A phospholipid derivative useful for the preparation of liposomes for efficient uptake of an antitumor agent or a gene intracellularly by a target tumor cell, which comprises a residue of an alcohol compound and a residue of a phospholipid, and comprising a peptide between the residue of an alcohol compound and the residue of a phospholipid, and wherein (a) the alcohol compound is an alcohol compound selected from poly(alkylene glycols) and the like, (b) the phospholipid is a phospholipid selected from phosphatidylethanolamines, phosphatidylcholines, phosphatidylserines and the like, and (c) the peptide is a peptide comprising a substrate peptide that can serve as a substrate of a matrix metalloproteinase, provided that one amino acid residue or an oligopeptide containing 2 to 8 amino acid residues may bind to one or both ends of the substrate peptide.

1 . A phospholipid derivative comprising a residue of an alcohol compound and a residue of a phospholipid, and comprising a peptide between the residue of an alcohol compound and the residue of a phospholipid, wherein
 (a) the alcohol compound is an alcohol compound selected from the group consisting of poly(alkylene glycols), glycerins, and polyglycerins,   (b) the phospholipid is a phospholipid selected from the group consisting of phosphatidylethanolamines, phosphatidylcholines, phosphatidylserines, phosphatidylinositols, phosphatidylglycerols, cardiolipins, sphingomyelins, ceramide phosphorylethanolamines, ceramide phosphorylglycerols, ceramide phosphorylglycerol phosphates, 1,2-dimyristoyl-1,2-deoxyphosphatidylcholines, plasmalogens and phosphatidic acids, and   (c) the peptide is a peptide comprising a substrate peptide that can serve as a substrate of a matrix metalloproteinase, provided that one amino acid residue or an oligopeptide containing 2 to 8 amino acid residues may bind to one or both ends of the substrate peptide.   
   
   
       2 . The phospholipid derivative according to  claim 1 , wherein the alcohol compound is a poly(alkylene glycol). 
   
   
       3 . The phospholipid derivative according to  claim 1 , wherein the phospholipid is a phosphatidylethanolamine. 
   
   
       4 . The phospholipid derivative according to  claim 1 , wherein the peptide is a peptide containing Val-Pro-Leu-Ser-Leu-Tyr-Ser-Gly. 
   
   
       5 . The phospholipid derivative according to  claim 1 , wherein the alcohol compound is a poly(ethylene glycol), the phospholipid is dioleoylphosphatidylethanolamine, and the peptide contains Gly-Gly-Gly as a linker. 
   
   
       6 . The phospholipid derivative according to  claim 1 , wherein the peptide is Gly-Gly-Gly-Val-Pro-Leu-Ser-Leu-Tyr-Ser-Gly-Gly-Gly-Gly. 
   
   
       7 . A lipid membrane structure comprising the phospholipid derivative according to  claim 1  as a component lipid. 
   
   
       8 . The lipid membrane structure according to  claim 7 , which is a liposome. 
   
   
       9 . The lipid membrane structure according to  claim 7 , which retains an antitumor agent or a gene for gene therapy of a malignant tumor. 
   
   
       10 . The lipid membrane structure according to  claim 9 , wherein the gene is a gene selected from the group consisting of antisense oligonucleotide, antisense DNA, antisense RNA, shRNA, and siRNA involved in angiogenesis or cell proliferation in malignant tumor, and a gene coding for a physiologically active substance including enzymes and cytokines, antisense RNA, shRNA, or siRNA. 
   
   
       11 . A pharmaceutical composition for therapeutic treatment of a malignant tumor, which contains the lipid membrane structure according to  claim 9 .